Eric RF Meffre PhD

Research Interests

Research Summary

The long range goal of our research is to further elucidate the mechanisms that regulate B cell tolerance in healthy humans and that are altered in patients with autoimmune diseases. The working hypothesis is that B cells from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) patients suffer from intrinsic signaling defects that result in a central failure to remove autoreactive B cells. In addition, alterations in T cell/dendritic cell functions may affect the counterselection of autoreactive B cells in the periphery. We are currently studying patients with CD19, TACI, ICOS, Fas, and AID gene defects to identify the roles of these molecules in the establishment of B cell tolerance. The involvement of NKT and Treg cells on peripheral B cell tolerance is currently being assessed by analyzing XLP patients who display no NKT cells and IPEX patients with Foxp3-deficiency in which no functional Treg cells develop resulting in severe autoimmune manifestations. Finally, we aim to characterize gene expression profiles using Affimetrix gene chips in unstimulated and BCR-stimulated RA and T1D B cells and compare them to those from healthy donor B cells to potentially identify defective pathways through genes that would fail to be properly regulated.

Extensive Research Description

Autoantibody production is a characteristic of most autoimmune
diseases including rheumatoid arthritis (RA), systemic lupus
erythematosus (SLE) and type 1 diabetes (T1D). These autoantibodies
appear in the serum many years before the onset of clinical disease
suggesting an early break in B cell tolerance. We previously
established in healthy donors that random V(D)J recombination produce
large numbers of autoreactive antibodies. Most developing B cells that
express polyreactive antibodies or B cell receptors (BCRs) are silenced
in the bone marrow, and additional autoreactive B cells are removed in
the periphery. We recently analyzed B cell tolerance in RA patients by
testing the specificity of recombinant antibodies cloned from single B
cells. RA patients exhibit defective central and peripheral B cell
tolerance checkpoints that result in the accumulation of self-reactive
mature naïve B cells, likely contributing to the pathogenesis of this
disease. Yet the mechanisms that lead to the generation and survival
of these autoreactive mature naïve B cells in RA patients are unknown.

Defects
in BCR signaling have been reported in B cells from SLE patients who
also suffer from defective central and peripheral B cell tolerance
checkpoints, suggesting that BCR signaling may play an important role
in counterselecting self-reactive B cells. By studying X-linked
agammaglobulinemia (XLA) patients who carry mutations in the BTKgene that encodes an essential BCR signaling component, we demonstrated
that Btk and therefore BCR signaling is essential in regulating
thresholds for human central B cell tolerance. In addition, developing
anti-nuclear B cells from IRAK-4- and MyD88-deficient patients failed
to be counterselected and demonstrated an essential role for Toll-like
receptors in the establishment of human B cell tolerance. Moreover, we
recently reported that CD40ligand (CD40L)-and MHC class II-deficient
patients who accumulated autoreactive B cells in their mature B cell
compartment displayed decreased numbers of regulatory (Treg) and NK T
cells in their blood suggesting that these cells may be involved in the
establishment of peripheral B cell tolerance in humans.

The
long range goal of our research is to further elucidate the mechanisms,
molecules and cells that regulate B cell tolerance in healthy humans
and that are altered in patients with autoimmune diseases. The working
hypothesis is that B cells from RA, SLE and potentially T1D patients
suffer from intrinsic signaling defects that result in a central
failure to remove autoreactive B cells. In addition, alterations in T
cell/dendritic cell functions may affect the counterselection of
autoreactive B cells in the periphery. We are currently studying B cell
tolerance in patients with CD19, TACI, ICOS, Fas, AID, uracil-DNA
glycosylase (UNG) gene defects to identify new pathways and molecules
required for the establishment of B cell tolerance. The role of NKT
and Treg cells on peripheral B cell tolerance is currently being
assessed by analyzing B cell tolerance checkpoints in two primary
immunodeficiencies, XLP and IPEX. XLP patients suffer from defective
SAP (SLAM associated protein) gene and display normal Treg cells but no
NKT cells whereas IPEX patients suffer from Foxp3-deficiency in which
no functional Treg cells develop resulting in severe autoimmune
manifestations.

Finally, we aim to characterize gene
expression profiles using Affimetrix gene chips in unstimulated and
BCR-stimulated RA and T1D B cells and compare them to those from
healthy donor B cells to potentially identify defective pathways
through genes that would fail to be properly regulated.